Pharmaceutical formulation for use in hiv therapy

ABSTRACT

The invention discloses a formulation prepared by granulating at least one anti-retro viral drug and at least one pharmaceutically acceptable additive, using an organic solvent; milling the product; finally processing the milled product to form tablets or capsules.

FIELD OF INVENTION

The present invention relates to a pharmaceutical formulation and inparticular to pharmaceutical formulations for use in HIV therapy. Italso discloses the processes to make the same. The invention has beendeveloped primarily for use as a formulation to be used for treatment inHIV therapy and will be described hereinafter with reference to thisapplication. Also disclosed is an improved bottle pack for storing theformulations. However, it will be appreciated that the invention is notlimited to this particular field of use.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Any discussion of the prior art throughout the specification should inno way be considered as an admission that such prior art is widely knownor forms part of the common general knowledge in the field.

There are multiple formulations known for use in HIV treatment therapy.The active substance Ritonavir [NORVIR soft gelatin capsule] ischaracterized by low aqueous solubility, a lack of bioavailability whengiven in the solid state, instability once in solution under ambientconditions and a metallic taste. U.S. Pat. No. 5,484,801 discloses aformulation wherein Ritonavir formulation has been optimized withrespect to the vehicle, which essentially is a solvent comprising amixture of (1) (a) a solvent selected from propylene glycol andpolyethylene glycol or (b) a solvent selected frompolyoxyethyleneglycerol triricinoleate, polyethylene glycol 40hydrogenated castor oil, fractionated coconut oil, polyoxyethylene (20)sorbitan monooleate and 2-(2-ethoxyethoxy) ethanol or (c) a mixturethereof and (2) ethanol or propylene glycol to improve thebioavailability.

Whereas Kaletra® is a formulation of two HIV protease inhibitors[Lopinavir and Ritonavir] in a single formulation. Till recently, thisformulation was available in a soft gel capsule, embodied in the patentU.S. Pat. No. 6,458,818 granted to Abbott. The patent covers a solutionof Lopinavir and Ritonavir in a long chain fatty acid organic solvent.This soft gel formulation has been criticized due to stability problemsand need for keeping the formulation in refrigerated condition. Abbotthas now introduced a new tablet formulation for combined administrationof Lopinavir and Ritonavir, instead of the previously known soft gelformulation. It has also filed patent applications related to thistablet formulation. For instance, WO2005039551 covers a combination ofLopinavir and Ritonavir in a water soluble polymer and surfactantwherein the tablet is formulated by melt extrusion process.Specifically, the disclosed process comprises following steps:

-   -   a) preparing a mixture of combination HIV protease inhibitors, a        water-soluble polymer and a surfactant,    -   b) feeding the mixture in a twin screw extruder while        maintaining a high temperature [133° C.] to form a homogeneous        melt,    -   c) feeding this melt to a calendar with counter rotating rollers        to be pressed into tablets.

HIV therapy formulations need to be made in the most economical mannerthereby reducing the final prices for AIDS patients across the world,especially in third world and developing countries. The aboveformulation and related melt extrusion process on account of itsrequiring expensive extrusion machinery & use of multiple surfactants [NVinyl pyrrolidone and Sorbitan monolaureate or polyoxyethyleneglyceroloxystearate] may not necessarily result in an economical formulation.Also, since the disclosed process requires heating the drug constituentsto high temperatures [exceeding 100° C.] it may possibly result indegradation of the drug constituents.

OBJECTS OF THE INVENTION

It is an object of the present invention to overcome or ameliorate atleast one of the disadvantages of the prior art, or to provide a usefulalternative.

It is an object of the invention in its preferred form to provide aneconomical formulation for administration of at least one anti-retroviral drug.

It is an object of the invention in its preferred form to provide aneconomical formulation for administration of a plurality of anti-retroviral drugs in a single formulation.

It is an object of the invention in its preferred form to provide aneconomical formulation for administration of a plurality of proteaseinhibitors in a single formulation.

It is an object of the invention in its preferred form to provide aneconomical formulation for administration of Lopinavir and Ritonavir ina single formulation.

It is another object of the invention to provide a formulation whichdoes not require use of expensive melt extrusion equipment.

It is another object of the invention to provide a formulation whichdoes not require heating the drug constituents and thereby reducechances of degradation of the drug constituents.

It is a further object of the invention to provide an improved bottlepack for storing the formulations wherein the desiccant is packed withinthe closure of the bottle.

SUMMARY OF THE INVENTION

According to the invention there is provided a pharmaceuticalformulation for use in HIV therapy. According to one aspect of theinvention there is also provided a process to make the same.

As presently contemplated, in one broad form, the invention provides aprocess to make a pharmaceutical formulation comprising the followingsteps:

-   -   a. granulating at least one anti-retro viral drug and at least        one pharmaceutically acceptable additive such as a solubilizing        agent, using an organic solvent;    -   b. milling product of step [a];    -   c. compressing milled product of step [b] into tablets or        filling it into capsules.

Another aspect of the invention provides for a pharmaceuticalformulation prepared by a process disclosed above.

As presently contemplated, in another broad form the invention providesa process to make a pharmaceutical formulation comprising the followingsteps:

-   -   a. granulating a plurality of anti-retro viral drugs and at        least one pharmaceutically acceptable additive such as a        solubilizing agent, using an organic solvent;    -   b. milling the granules so formed;    -   c. processing the milled product into pharmaceutical        formulations such as tablets or capsules.

Another aspect of the invention provides for a pharmaceuticalformulation prepared by a process disclosed above.

Another aspect of the invention provides for process to makepharmaceutical formulation comprising the steps of:

-   -   a) mixing a plurality of anti-retro viral drugs with        pharmaceutical additives such as a solubilizing agent in an        organic solvent;    -   b) mixing a glidant and a muco-adhesive excipients in a solvent;    -   c) mixing product of step [a] and [b]    -   d) drying product of step [c];    -   e) milling product of step [d];    -   f) processing the milled product into pharmaceutical        formulations such as tablets or capsules.

Another aspect of the invention provides for a pharmaceuticalformulation prepared by a process described above.

BRIEF DESCRIPTION OF THE DRAWINGS

A preferred embodiment of one the aspects of the invention, i.e. thebottle pack for packing anti retro viral formulations will now bedescribed, by way of example only, with reference to the accompanyingdrawings in which:

FIG. 1 is a cross section view of a closure of the bottle pack accordingto the invention, while FIG. 1A shows a cross section view of analternative closure of the bottle pack.

In FIG. 1, closure [2] has a receptacle [3] for holding a desiccant [4]within closure itself. Here the receptacle [3] is a distinct part thatis attached/fixed to the closure [2].

While in the embodiment in FIG. 1A, the receptacle [3] is molded withinthe closure [2] itself such that it is a permanent part of the closurebody.

DETAILED DESCRIPTION INCLUDING PREFERRED EMBODIMENTS OF THE INVENTION

The bioavailability of drugs is directly related to their dissolution inthe gastrointestinal fluids. The anti retro viral drug may be selectedfrom HIV protease inhibitor[s] such as Lopinavir, Ritonavir, Saquinavir,Nelfinavir, Atazanavir, Indinavir, Tipranavir, Palinavir, Amprenavir,Fosemaprenavir & Darunavir etc. Also, other anti-retro viral drugs suchas Nucleoside Reverse Transcriptase Inhibitors [NRTIs] or Non-NucleosideReverse Transcriptase Inhibitors [NNRTIs] can be effectively employedwithout undue experimentation in the present invention to render astable and economical formulation. For e.g. Nucleoside ReverseTranscriptase Inhibitors could be selected from Abacavir, Didanosine,Emtricitabine, Lamivudine, Stavudine, Zidovudine & Zalcitabine.Similarly, NNRTIs could be selected from Nevirapine, Delavirdine orEfavirenz. Also, Nucleotide Reverse Transcriptase Inhibitors such asTenofovir could also be employed. The preferred single drug isRitonavir.

Thus, even a combination of any of the above anti-retro viral drugs andat least one pharmaceutically acceptable additive granulated in anorganic solvent subsequently milled, and subsequently processed topharmaceutical formulations such as tablets or capsules would also comewithin the ambit of the process of present invention. The preferred drugcombination is Lopinavir:Ritonavir in a proportion of 4:1.

Formulation methods such as melt extrusion, spray drying and solventevaporation with melt extrusion have been suggested to make tabletformulations of Lopinavir and Ritonavir combination. These methods needspecialized equipment and heating at high temperatures.

The present invention avoids factors such as use of specialised meltextrusion equipment, processing at high temperatures and provides astable, solid pharmaceutical dosage form comprising at least oneprotease inhibitor admixed with pharmaceutical additives, granulated inan organic solvent, milled and finally processing the milled productinto pharmaceutical formulations such as tablets or capsules. Thus,using wet granulation manufacturing process and standard equipment anovel, stable and economical formulation for delivering at least oneanti-retro viral drug is disclosed. The formulation may also consist ofa plurality of HIV protease inhibitors. The process of granulation iscarried out in presence of an organic solvent. The process sequenceconsists broadly of:

-   -   a) Mixing at least one anti-retro viral drug with an organic        solvent and a pharmaceutical additives, preferably a        solubilizer;    -   b) Mixing and sifting excipients[s] and then adding them to an        organic solvent, preferably the same as used in step [a]. The        excipients can be one that has muco-adhesive property such as        HPMC along with more excipients such as a glidant for e.g.        colloidal silicon dioxide;    -   c) Mixing the above two to form a uniform thick paste;    -   d) Drying the paste using vacuum or nitrogen stream or heat;    -   e) Milling the above dried mass;    -   f) Optionally, adding lubricants to the milled mixture.    -   g) This milled product can be compressed into tablets or filled        in capsules.

It is to be noted that all the steps [a] and [b] can be combined, suchthat all the items are mixed in the organic solvent to form a paste.Also, instead of one drug, more than one drug can also be mixed in step[a]. The process may be is carried out in a Nitrogen atmosphere.Examples have been provided that will clarify the above general processsteps.

The solvents to be used are organic solvents such as methanol,dichloromethane, ethanol, acetone, ethyl acetate, isopropyl alcohol,preferably, dichloromethane.

The term ‘pharmaceutically acceptable additive’ includes‘pharmaceutically acceptable excipient’ within its ambit and thesingular term includes plural as well. Pharmaceutically acceptableadditives such as a solubilizing agent or a combination of solubilizingagents, pharmaceutically acceptable excipients having muco-adhesiveproperties, a glidant, a lubricant and a disintegrating agent can beadded to further enhance the properties of the formulation. Thesolubilizing agent may be either a pharmaceutically acceptable polymeror a pharmaceutically acceptable copolymer or any pharmaceuticallyacceptable fatty acid ester, used singly or in combination and shouldideally be dispersible or soluble in organic solvent selected. Examplesof solubilizing agents are glyceryl mono-oleate,polyethylene-polypropylene glycol copolymer [Poloaxamer], sorbitanesters, polyoxyl castor oil, polyoxyethylene stearates. Commerciallyavailable substances such as Poloaxamer 124/407 can also serve as thesolubilizing agent. The pharmaceutically acceptable excipient havingmuco-adhesive properties include cellulose ethers, polyacrylic acid,polymethacrylates, poloxamer, polydextrose, copovidone, polyvinylalcohol, chitosan, guar gum, sodium alginate, dextrin, polyethyleneglycol etc. An e.g. for excipient having muco-adhesive property isHydroxypropylmethyl cellulose [HPMC, commercially available asHypromellose].

Glidants improve the flowability of the powder making up the tabletduring production. Glidants can be selected from selected from the groupconsisting of: silicon dioxide, colloidal silicon dioxide, fumed silicondioxide, sodium aluminosilicate, calcium silicate, powdered cellulose,microcrystalline cellulose, corn starch, sodium benzoate, calciumcarbonate, magnesium carbonate, asbestos free talc, metallic stearates,calcium stearate, magnesium stearate, zinc stearate, stearowet C,starch, starch 1500, magnesium lauryl sulfate, or magnesium oxide, wherecolloidal silicon dioxide is the preferred glidant.

Lubricants may be selected from the group of magnesium stearate, calciumstearate, sodium stearyl fumarate, stearic acid, hydrogenated cottonseedoil, sodium benzoate, sodium lauryl sulfate etc.

Skilled professionals will appreciate that although the examplesdisclosed below involve use of rapid mixer granulator, alternativeequipments like planetary mixers, ribbon blender etc. can also beemployed without any undue experimentation to get the desired results.Although the invention has been described with reference to specificexamples, it will be appreciated by those skilled in the art that theinvention may be embodied in other forms.

In one aspect of the invention, the pharmaceutical dosage formcomprises:

-   -   a) from about 5 to about 30% by weight of the total dosage form        (preferably from about 10 to about 25% by weight of the total        dosage form) of at least one anti-retro viral drug;    -   b) from about 10 to about 40% by weight of the total dosage form        (preferably from about 10 to about 25% by weight of the total        dosage form) of a solubilizing agent (or any combination of        thereof)    -   c) from about 3 to about 70% by weight of the total dosage form        (preferably from about 50 to about 65% by weight of the total        dosage form) of a muco-adhesive excipient (or any combination of        thereof)    -   d) quantities of lubricants and glidants are to be added using        conventional knowledge.    -   d) solvent for granulation is also added in terms of standard        wet granulation parameters.

The milled product post granulation is processed further, for e.g. itcan be compressed to form tablets or filled into capsules, usingstandard machines/processes, known to persons skilled in the art.

In its preferred form, the process involves:

-   -   a) mixing lopinavir and ritonavir and at least one solubilizing        agent, in the presence of an organic solvent;    -   b) mixing a polymer and glidant in an organic solvent;    -   c) mixing the products of step[a] and [b] to form a uniform        paste,    -   d) drying the paste;    -   e) milling the dried product;    -   f) processing the milled product into pharmaceutical        formulations such as tablets or capsules.

The formulations of the present invention can be stored in ordinaryHDPE/plastic bottles. However, we have disclosed an improved bottle packfor storing such formulations. Normal bottles have a closure with acavity that closes around the bottle's neck such that the neck of thebottle fits within the closure's cavity. When medicines are stored inbottles, a desiccant is also added to absorb moisture. But this practicemeans an additional processing step on the packing line as also the riskthat some patients may ingest the desiccant confusing it with medicine.

Our improved bottle pack consists of a bottle and a closure that has areceptacle within its cavity such that the receptacle holds thedesiccant. The closure is fitted by the bottle pack supplier with adesiccant within the receptacle and hence there is no need for puttingin a desiccant at the time of filling the medicines. The receptacle maybe formed as a part of the closure itself or it may be attached/addedinside the closure. The receptacle may fixed within the closure or itmay be removably fixed within the closure. FIG. 1 illustrates a closurewhere the receptacle is added inside the closure, while FIG. 1Aillustrates a closure where the receptacle is a part of the closure bodyitself.

Such a closure with a pre-fitted desiccant has the following advantages:

-   -   a) The desiccant in the top portion of the bottle helps in        capturing all the moisture in the head space much faster as        moisture is vaporizing in an upward direction. In a normal        bottle where the desiccant sachet is put inside along with the        pharmaceutical product, it absorbs the moisture whenever        moisture settles down.    -   b) Different quantities of desiccant can be fixed within the        receptacle without changing the bottle/closure dimensions.    -   c) The present closure eliminates one extra operation of        inserting the desiccant on machine and also reduced inventory,        reduced storage space as this desiccant i.e. pre-filled inside        the closures.

EXAMPLE 1 Wet Granulation Process

Ingredient % w/w Lopinavir 20.0 Ritonavir 5.0 Poloxamer 124 12.0Hypromellose (6 cps) 58.0 Colloidal silicon dioxide 3.0 Sodium stearylfumarate 2.0 Dichloromethane q.s.

Manufacturing Steps:

-   -   a Lopinavir, Ritonavir and Poloxamer 124 were dissolved in        dichloromethane;    -   b. Colloidal silicon dioxide and hypromellose were sifted        through a size 20 mesh;    -   c. The mixture from step [b] was loaded into a rapid mixer        granulator;    -   d. The drug mixture of step [a] was added to the granulator and        processed;    -   e. The product was dried under vacuum at about 40° C.;    -   f. The dry product was then milled in a multimill;    -   g. Sodium lauryl sulfate was mixed with milled product and        sifted for about 10 minutes;    -   h. This sifted product was finally compressed into tablets.

EXAMPLE 2

Ingredient % w/w Lopinavir 20.0 Ritonavir 5.0 Glyceryl mono-oleate 4.0Poloxamer 407 63.0 Colloidal silicon dioxide 5.0 Sodium stearyl fumarate2.0 Talc 1.0 Methanol q.s.

Manufacturing Steps:

-   -   a. Lopinavir, Ritonavir and glyceryl mono-oleate were dissolved        in methanol;    -   b. Colloidal silicon dioxide and Poloxamer 407 were sifted        through a size 20 mesh;    -   c. The mixture from step [b] was loaded into a rapid mixer        granulator;    -   d. The drug solution of step [a] was added to the granulator and        processed;    -   e. The product was dried under vacuum at about 40° C.;    -   f. The dry product was then milled in a multimill;    -   g. Sodium lauryl sulfate and talc was mixed with milled product        and sifted for about 10 minutes;    -   h. This sifted product was finally compressed into tablets.

EXAMPLE 3

Ingredient % w/w Lopinavir 15.0 Ritonavir 3.75 Glyceryl monooleate 5.0Poloxamer 407 15.0 Hypromellose (3 cps) 55.25 Colloidal silicon dioxide3.0 Hydrogenated cottonseed oil 2.0 Sodium lauryl sulfate 1.0 Methanolq.s.

Manufacturing Steps:

-   -   a. Lopinavir, Ritonavir and glyceryl monooleate were dissolved        in methanol;    -   b. Colloidal silicon dioxide and hypromellose were sifted        through a size 20 mesh;    -   c. The mixture from step [b] was loaded into a rapid mixer        granulator;    -   d. The drug solution of step [a] was added to the granulator and        processed;    -   e. The product was dried under vacuum at about 45° C.;    -   f. The dry product was then milled in a multimill;    -   g. Sodium lauryl sulfate and hydrogenated cottonseed oil was        mixed with milled product and sifted for about 10 minutes;    -   h. This sifted product was finally compressed into tablets.

EXAMPLE 4

Ingredient % w/w Lopinavir 22.0 Ritonavir 5.5 Sorbitan laureate 10.0Poloxamer 407 56.5 Colloidal silicon dioxide 3.0 Sodium stearyl fumarate3.0 Ethyl acetate q.s.

Manufacturing Steps:

-   -   a. Lopinavir, Ritonavir and sorbitan laureate were dissolved in        ethyl acetate;    -   b. Colloidal silicon dioxide and Poloxamer 407 were sifted        through a size 20 mesh;    -   c. The mixture from step [b] was loaded into a rapid mixer        granulator;    -   d. The drug solution of step [a] was added to the granulator and        processed;    -   e. The product was dried under vacuum at about 45° C.;    -   f. The dry product was then milled in a multimill;    -   g. Sodium lauryl sulfate was mixed with milled product and        sifted for about 10 minutes;    -   h. This sifted product was finally compressed into tablets.

EXAMPLE 5

Ingredient % w/w Lopinavir 16.4 Ritonavir 4.1 Sorbitan laurate 6.8Copovidone 70.1 Colloidal silicon dioxide 1.6 Sodium stearyl fumarate1.0 Ethyl acetate q.s.

Manufacturing Steps:

-   -   a. Lopinavir, Ritonavir and sorbitan laurate were dissolved in        ethyl acetate;    -   b. Colloidal silicon dioxide and Copovidone were sifted through        a size 20 mesh;    -   c. The mixture from step [b] was loaded into a rapid mixer        granulator;    -   d. The drug solution of step [a] was added to the granulator and        processed;    -   e. The product was dried under vacuum at about 40° C.;    -   f. The dry product was then milled in a multimill;    -   g. Sodium stearyl sulfate was mixed with milled product and        sifted for about 10 minutes;    -   h. This sifted product was finally compressed into tablets.

EXAMPLE 6

Ingredient % w/w Lopinavir 16.4 Ritonavir 4.1 Sorbitan laurate 6.8Copovidone 70.1 Colloidal silicon dioxide 1.6 Sodium stearyl fumarate1.0 Dichloromethane q.s.

-   -   a. Lopinavir, Ritonavir, Sorbitan monolaurate, Copovidone and        colloidal silicon were put in a rapid mix granulator and mixed;    -   b. Dichloromethane was added and the mixture was processed till        a uniform wet mass was formed;    -   c. The wet mass was dried under vacuum at about 45° C.;    -   d. The dry product was then milled in a comminuting mill;    -   e. Sodium lauryl sulfate was mixed with milled product and        product was finally compressed into tablets.

An alternative embodiment of the invention is disclosed below:

EXAMPLE 7

Ingredient % w/w Ritonavir 10.0 Poloxamer 124 10.0 Copovidone 77.0Colloidal silicon dioxide 2.0 Sodium stearyl fumarate 1.0Dichloromethane q.s.

-   -   a. Ritonavir, copovidone colloidal silicon dioxide and Poloxamer        124 were put in a planetary mixer and mixed for 30 minutes    -   b. Dichloromethane was added and the mixture was mixed        continuously till a uniform wet mass was obtained.    -   c. The wet mass was then removed from the planetary mixer and        transferred to the tray dryer and dried at 40-50° C. preferably        under vacuum.    -   d. The dried material was then milled using comminuting mill.    -   e. The sodium stearyl fumarate was mixed with milled material        and finally compressed into tablets.

An alternative formulation is disclosed below:

EXAMPLE 8

Ingredient % w/w Ritonavir 10.0 Sorbitan monolaurate 14.0 Copovidone71.0 Colloidal silicon dioxide 2.0 Sodium stearyl fumarate 1.0

-   -   a. Ritonavir, copovidone colloidal silicon dioxide and Sorbitan        monolaurate were put in a jacketed vessel and mixed for 30        minutes    -   b. The mixture was heated with constant stirring till the        mixture temperature reached the melting point of Ritonavir.    -   c. The heating was stopped and the material was allowed to cool        down.    -   d. The dried material was then milled using comminuting mill.    -   e. The sodium stearyl fumarate was mixed with milled material        and finally compressed into tablets.

EXAMPLE 9

Ingredient % w/w Lopinavir 20.0 Ritonavir 5.0 Poloxamer 124 12.0Hypromellose (6 cps) 58.0 Colloidal silicon dioxide 3.0 Sodium stearylfumarate 2.0 Dichloromethane q.s.

-   -   a. Lopinavir, Ritonavir and poloxamer were dissolved in        dichloromethane.    -   b. Colloidal silicon dioxide and hypromellose were sifted        through 20 mesh.    -   c. All the material from [b] was loaded in a Stainless steel        vessel fitted with agitating device/stirrer, containing a small        quantity of the solvent.    -   d. The product of [step c] was mixed with the drug solution        [step a] in the stainless steel vessel till a uniform thick        paste was formed.    -   e. The paste was dried at about 40° C. under vacuum [a nitrogen        stream could also be used].    -   f. The dried mass was milled using multimill.    -   g. The milled granules were mixed with sodium lauryl sulfate for        10 minutes and compressed into the tablets.

EXAMPLE 10

Ingredient % w/w Lopinavir 15.0 Ritonavir 3.75 Glyceryl monooleate 5.0Poloxamer 407 15.0 Hypromellose (3 cps) 55.25 Colloidal silicon dioxide3.0 Hydrogenated cottonseed oil 2.0 Sodium lauryl sulfate 1.0 Methanolq.s.

-   -   a. Lopinavir, Ritonavir, poloxamer glyceryl monooleate and        copovidone were dissolved in methanol.    -   b. The methanolic solution was then spray dried at 70° C.    -   c. The spray dried powder was then mixed with colloidal silicon        dioxide, hydrogenated cottonseed oil and sodium lauryl sulfate        for 10 minutes    -   d. This was then compressed into the tablets.

EXAMPLE 11

Ingredient % w/w Lopinavir 16.4 Ritonavir 4.1 Sorbitan laurate 6.8Copovidone 70.1 Colloidal silicon dioxide 1.6 Sodium stearyl fumarate1.0 Dichloromethane q.s.

-   -   a. Lopinavir, Ritonavir and sorbitan laurate were dissolved in        dichloromethane.    -   b. Colloidal silicon dioxide and Copovidone were sifted through        20 mesh and loaded into in a suitable stainless steel container        fitted with agitating device/stirrer and containing a small        quantity of the solvent.    -   c. The powdered blend in the stainless steel container was mixed        with the drug solution till a homogeneous slurry was formed.    -   d. The slurry was dried at about 40° C.    -   e. The dried mass was milled using multimill.    -   f. The milled granules were mixed with sifted sodium stearyl        fumarate with for 10 minutes and compress into the tablets.

1-30. (canceled)
 31. A process of preparing a pharmaceutical formulation, comprising essentially of: a. dissolving or suspending at least one anti-retro viral drug and optionally at least one pharmaceutically acceptable additive, in an organic solvent to obtain a solution or dispersion; b. drying said solution or dispersion to obtain granules; c. optionally lubricating said granules; d. compressing said granules into tablets or filling it into capsules.
 32. The process according to claim 31, wherein said anti-retro viral drug is selected from the group consisting of HIV protease inhibitors, Nucleoside Reverse Transcriptase Inhibitors and/or Non-Nucleoside Reverse Transcriptase Inhibitors and their mixtures.
 33. The process according to claim 32, wherein said anti-retro viral drug is lopinavir, ritonavir or a combination thereof.
 34. The process according to claim 31, wherein said pharmaceutically acceptable additive is selected from a group consisting of: a. solubilizing agents; b. muco-adhesive agents and optionally c. glidants.
 35. The process according to claim 34, wherein said solubilizing agent is selected from a group consisting of: polyethylene-polypropylene glycol copolymer (Poloaxamer), glyceryl mono-oleate, sorbitan esters, polyoxyl castor oil, and polyoxyethylene stearates.
 36. The process according to claim 34, wherein said muco-adhesive agent is selected from a group consisting of: cellulose ethers, polyacrylic acid, polymethacrylates, polydextrose, co-povidone, polyvinyl alcohol, chitosan, guar gum, sodium alginate, dextrin and polyethylene glycol.
 37. The process according to claim 31, wherein said organic solvent is selected from a group consisting of: dichloromethane, methanol, ethanol, acetone, ethyl acetate, and isopropyl alcohol.
 38. The process according to claim 31, wherein said pharmaceutical formulation additionally contains acceptable pharmaceutical excipients selected from a group consisting of: diluents, binders, disintegrants, and surfactants.
 39. The process according to claim 33, wherein lopinavir and ritonavir is present in a proportion of 4:1 by weight.
 40. A method of treating an HIV infection comprising administering a pharmaceutical composition prepared by the process of claim 31 to a mammal in need of such treatment.
 41. A process of preparing a pharmaceutical formulation, consisting essentially of: a. dissolving lopinavir, ritonavir, poloxamer, glyceryl mono-oleate and povidone, in methanol to obtain a solution; b. drying said solution to obtain granules; c. lubricating said granules with colloidal silicon dioxide, hydrogenated cotton seed oil and sodium lauryl sulfate; d. compressing said lubricated granules into tablets or filling it into capsules.
 42. A method of treating an HIV infection comprising administering a pharmaceutical composition prepared by the process of claim 41 to a mammal in need of such treatment.
 43. A bottle-pack for storing an anti-retro viral composition, wherein said bottle pack comprises a body having a mouth opening and a closure, said closure being designed to hold a desiccant within itself.
 44. The bottle-pack according to claim 43, wherein said closure has a cavity to hold said desiccant.
 45. The bottle-pack as claimed in claim 44, wherein said cavity is detachable or fixed permanently within said closure. 